Preclinical discovery and development of adalimumab for the treatment of rheumatoid arthritis.

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by progressive joint disorders with significant pain and stiffness. In the past, RA was a difficult -to-treat ailment, but nowadays with the advent of biologics and better treatment strategies, disease remission is an achievable goal. Tumor necrosis factor α (TNFα) inhibitors were the first category of biologics to emerge with adalimumab being the first fully human TNFα.Areas covered: the authors provide an overview of the historical events that led to the discovery of TNFα inhibitors and more specifically the drug adalimumab. Several key trials are presented regarding the safety of the drug as well as its successful journey, but there is also a narrative description of the drug's future after patent expiration.Expert opinion: Adalimumab is a fully human TNFα inhibitor with a fairly rapid onset of action. It has a generally good safety and efficacy profile. Clinicians must be aware of the possible side effects and treat them in a timely manner or discontinue the drug where appropriate. Due to the success of the bio-originator adalimumab, a multitude of biosimilars have emerged but not, thus far, for all of the indications of the bio-originator.

Are biosimilars approved for use in psoriasis safe enough to replace leading biologic therapies? A review.

Introduction: Many tumor necrosis factor (TNF)-alpha 'biosimilar' agents have been approved for the treatment of psoriasis and other autoinflammatory conditions. These biosimilars have the same structure as the originator biologic and have been shown to be equivalent in terms of safety and efficacy. However, given the method by which biosimilars are manufactured, they are not exact replicas of the originator, unlike generic forms of non-biologic medications. Therefore, there is controversy regarding whether these agents should be considered interchangeable with their originator biologics.Areas covered: The objective of this review is to summarize the safety data for each of the approved TNF-alpha biosimilars to determine whether or not these agents have appropriate safety profiles to replace their originator biologics.Expert opinion: Based on extrapolation of phase III investigations in patients with rheumatologic diseases, each of the approved anti-TNF agents have comparable efficacy, tolerability, and safety profiles to their originators. Studies in patients with psoriasis are more limited. Transitioning from a biologic to its biosimilar has also been shown to be similarly safe and immunogenetic compared to maintenance therapy with the originator. More post-marketing studies are needed to demonstrate the long-term safety in patients with psoriasis.

Current and Future Therapies for Psoriasis with a Focus on Serotonergic Drugs.

Psoriasis is a chronic immune-mediated skin disease, with a pathogenesis resulting from a combination of genetic and environmental factors. The pathogenesis of psoriasis is driven by the interaction between innate and adaptive immune cells and keratinocytes, in a complex process mediated by cytokines and other signaling molecules. This leads to an inflammatory process with increased proliferation of epidermal cells, neo-angiogenesis, and infiltration of white cells in the skin, which cause the characteristic psoriasis plaques. Several studies have suggested that the neurotransmitter serotonin, a key mediator between the skin and the neuroendocrine system, also plays an important role in the pathogenesis of psoriasis. Psoriasis often needs long-term treatment, which can be a burden. Thus, the choice of the treatment is crucial to increase the patients' adherence and quality of life. This review addresses the currently available systemic and topical treatments for psoriasis, used by themselves or combined with phototherapy. It particularly focuses on the importance of advanced drug delivery systems as a way to increase the drug penetration and retention in the skin, while also enhancing its solubility and stability. Finally, we discuss the role of the serotonin system in psoriasis, and summarize what is known about the effects of antidepressants, in particular specific serotonin reuptake inhibitors, on the physical symptoms of this disease.

Scientific rationale underpinning the development of biosimilar rituximab in hematological cancers and inflammatory diseases.

Sandoz rituximab (SDZ-RTX; Rixathon®; GP2013), a rituximab biosimilar, was approved in June 2017 in Europe in all indications of reference rituximab. The stepwise SDZ-RTX development program generated extensive physicochemical, structural, functional, and biological data demonstrating a match with reference rituximab on all clinically relevant attributes. A focused clinical development program followed, in two indications selected for sensitivity to detect potential differences versus reference rituximab: rheumatoid arthritis (pivotal pharmacokinetics and efficacy evaluation) and follicular lymphoma (pivotal efficacy/safety evaluation). These trials demonstrated highly similar pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity profiles. The totality of evidence for biosimilarity for SDZ-RTX, combined with knowledge that B-cell depletion is common to each approved indication, allowed SDZ-RTX approval for use in all indications of reference rituximab.

An update on the animal studies conducted for biosimilar approvals - Regulatory requirement vs actual scenario.

Nonclinical animal studies are considered as an integral part of biosimilar development program to demonstrate similarity and safety. We have compiled, reviewed and summarized animal studies conducted for European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) submission from 2006 till December 2018. The commonest animal studies conducted included repeat-dose toxicity study along with toxicokinetic, local tolerance and immunogenicity assessments, while the least common included primary pharmacodynamic, pharmacokinetic, safety pharmacology and single-dose toxicity studies. Animal studies were designed based on pharmacology of the drug, disease condition and innovator studies. Studies mostly used EU-sourced reference products as a comparator. For biosimilars approved both in the US and European Union (EU), similar data packages were submitted to these regions. Despite the regulatory guidelines allowing waiver of animal studies based on analytical data, animal studies have been conducted for almost all the approved biosimilars in the US and EU. There is an increasing need to re-assess the relevance of animal studies to support regulatory approval of biosimilars. Stepwise assessment for biosimilarity and conducting animal studies only if required at the right instance based on residual uncertainties may assist in optimizing animal study requirement for biosimilar development.

Price competition and reimbursement of biosimilar granulocyte-colony stimulating factor in Hungary.

Objectives: We analyzed the bid approach of the Hungarian National Health Insurance Fund Administration (NHIFA) based on the results of two consecutive bids on colony stimulating factor (CSF).Methods: The Hungarian NHIFA database was used to analyze the changes in the number of patients treated with CSF and reimbursement paid by NHIFA, 12 months preceding and following the bids.Results: 13,974 patients received granulocyte-CSF treatment during 12 months prior to bidding. A 4.5% decrease (13,352) and further 1.3% decrease (13,185) in the total number of patients were observed during the first and second years, respectively. The annual health insurance subsidy paid during 12 months prior to the bids was. 7.49 billion Hungarian Forint (HUF) or 26.8 million Euro (EUR). In the first year following the bid, we found a 3.3 billion HUF (12.4 million EUR) decrease in health insurance subsidy (44% reduction). A further 7.9% reduction was observed during the second year, resulting in an annual health insurance subsidy of 3.59 billion HUF (12.1 million EUR).Conclusion: During the 2 years bid (public procurement procedure), the National Health Insurance Fund Administration managed to reduce the health insurance subsidy paid for the reimbursement of both original and biosimilar G-CSF products.

Comparative safety assessments of the biosimilar APZ001 and Erbitux in pre-clinical animal models.

PURPOSE: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. METHODS: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. RESULTS: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. CONCLUSION: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.

Comparative safety assessments of the biosimilar APZ001 and Erbitux in pre-clinical animal models

Abstract Purpose: To evaluate the toxicity of Erbitux as well as its biosimilar APZ001 antibody (APZ001) in pre-clinical animal models including mice, rabbits and cynomolgus monkeys. Methods: We performed analysis of normal behavior activity, autonomic and non-autonomic nervous functions, nervous-muscle functions, nervous excitability and sensorimotor functions on CD-1 mice. Subsequently, we studied that effects of APZ001 and Erbitux on respiratory system, cardiovascular system and kidney in Cynomolgus monkey models and performed local tolerance experiments on New Zealand rabbits. Results: The comparisons between APZ001 and Erbitux showed no significant differences in mice autonomic nervous system, nervous muscle functions, non-autonomic nervous functions, nervous excitability and sensorimotor functions between treated and untreated group (p>0.05). APZ001 and Erbitux showed negative effect on CD-1 mice in the present of pentobarbital sodium anesthesia (p>0.05). Single administrations of high, medium or low doses of APZ001 did not lead to monkey urine volume alterations (p>0.05). In human tissues, APZ001 and Erbitux showed positive signals in endocardium, lung type II alveolar epithelial cell and surrounding vessels, but showed negative results in kidney and liver tissues. No hemolysis phenomenon and serious side-effects in vessels and muscles were observed in rabbits when administrated with APZ001 and Erbitux respectively. Conclusion: The safety comparisons between APZ001 antibody and Erbitux showed that these two antibodies showed highly similarities in mice, rabbits and cynomolgus monkey animal models in consideration of pharmaceutical effects, indicating APZ001 might be a suitable substitute for Erbitux.

A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival results.

BACKGROUND: The equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment. PATIENTS AND METHODS: Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period. RESULTS: Of 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59-1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ. CONCLUSIONS: Final safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).

Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer.

Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2-positive early breast cancer in the neoadjuvant setting ( ClinicalTrials.gov identifier: NCT02149524). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.

Biosimilar Products in the Modern U.S. Health Care and Regulatory Landscape.

Biosimilars have the potential to greatly reduce medication costs in the United States. As of July 1, 2017, 5 biosimilars have been approved by the FDA, but only 2 are available for purchase. This commentary outlines the efforts of an integrated health system to ensure biosimilar accessibility and discusses the current challenges and future implications. We highlight the implementation of a health plan policy and how a health system's formulary committee can encourage use while considering provider perceptions and operational challenges. In addition, we provide our perspective on potential implications for pricing, site of care, and pharmacy dispensing practices based on our experience with regulatory hurdles and market trends. Overall, we believe biosimilars are a good thing for the health care system, but their expected benefit may not be realized for years to come. DISCLOSURES: No outside funding supported this work. Affeldt reports advisory board membership with Janssen, and Skiermont reports membership with Amgen and McKesson. The other authors have nothing to disclose. Peterson and Budlong contributed the study concept and design and wrote the manuscript. Affeldt, Skiermont, Kyllo, and Heaton reviewed and revised the manuscript.

Fármacos biosimilares: un nuevo escenario en las terapias biológicas / Biosimilars: a new scenario in biologic therapies

No cabe duda de que los productos biológicos aportan un valor añadido a los sistemas de salud, aunque también plantean grandes interrogantes debido a su especial naturaleza, lo que obliga a ser muy rigurosos y exigentes en su control de calidad y seguimiento. Este hecho se ha visto reforzado por la entrada en escena de los fármacos biosimilares, cuyo menor coste está permitiéndoles alcanzar un mayor protagonismo en el mercado mundial. El propósito de este artículo es revisar en profundidad los principales interrogantes que se plantean en su producción, distribución y control, así como los aspectos más importantes relacionados con su seguridad en la práctica clínica. En este trabajo revisamos lo que representa la farmacovigilancia de estos productos, prestando especial atención a su trazabilidad, como herramienta fundamental para la detección precoz de acontecimientos adversos (AU)

There is no doubt that biologic therapies provide added value for health systems. However, due to their special nature, they also raise some questions that make highly rigorous and demanding quality control and monitoring of their use indispensable. This circumstance is reinforced with the appearance on the scene of biosimilars, which, given their lower cost, are having an increasing impact on the international market. The purpose of this article is to review the major issues posed by their manufacture, distribution and control systems, as well as the most important aspects related to their safety in clinical practice. In this report, we assess the pharmacovigilance of these products, with special attention to traceability, as a key tool to enable earlier detection of adverse events (AU)

CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial.

BACKGROUND: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. METHODS: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. FINDINGS: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4-53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1-56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0·04% [95% CI -0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). INTERPRETATION: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. FUNDING: Celltrion Inc.

Biosimilars in inflammatory bowel disease: A review of post-marketing experience.

Biologic compounds are obtained from living organisms or cell cultures by means of biotechnology methods. A similar biologic drug, commonly called biosimilar, is a product copied by a native approved biologic drug whose license has expired. Biosimilar drugs usually are marketed at a lower price and provide important financial savings for public healthcare systems. Some differences between biosimilars and original biologic drugs might exist but they are acceptable if they fall within defined "boundaries of tolerance": differences in some features between the two molecules are considered important only if clinical relevant. Considering that the efficacy of the innovator biologic drug has already been established, the clinical studies required for approval of a biosimilar could be reduced compared with those required for the approval of the originator. In this review, real life data available in inflammatory bowel disease patients treated with biosimilars are reported, documenting in general satisfactory outcomes, sustained efficacy and no sign of increased immunogenicity, although, further controlled data are awaited.

[Biosimilars in oncology: a therapeutic alternative to the reference products?] / Biosimilars in der Onkologie: Eine therapeutische Alternative zu Referenzarzneimitteln?

Biosimilar medicinal products (biosimilars) have been available in Europe for 10 years, allowing a wide use particularly in oncology. Biosimilars are being developed and approved by means of scientifically sound principles to assure close similarity with the reference products with regard to quality, efficacy, and safety. The scientific principles for establishing biosimilarity are the same as those for demonstrating comparability after a change in the manufacturing process of an already licensed biological. Nevertheless, many clinicians voiced concerns about biosimilars related to their pharmaceutical quality, efficacy (particularly in extrapolated indications), safety (especially immunogenicity), and interchangeability with the originator product. The availability of biosimilars would strengthen the economic competition on the pharmaceutical market, provide opportunities to improve healthcare access, and contribute to the financial sustainability of European healthcare systems. Biosimilars can be considered therapeutic alternatives to the reference product. To date, no data has been published revealing any disadvantages of the biosimilars' use. This article aims to acquaint clinicians, particularly oncologists and haematologists, with the biosimilar concept as they are going to be confronted with a constantly increasing number of biosimilars due to patent expirations in the near future. Furthermore, it provides information on scientific principles guiding biosimilar development and regulatory requirements. This should minimise unfounded fears and concerns among clinicians. Additionally, we provide information on the interchangeability between originator products and biosimilars to assist clinicians in making evidence-based, appropriate, and cost-effective treatment choices for their patients.